Geriatric nutritional risk index as a potential prognostic marker for patients with resectable pancreatic cancer: a single-center, retrospective cohort study

In pancreatic cancer, postoperative complications (POCs) are associated with disease outcomes. The geriatric nutritional risk index (GNRI) is known to predict POCs after pancreatoduodenectomy (PD) or distal pancreatectomy (DP) in patients with hepatobiliary pancreatic tumors, including pancreatic cancer. Through POC occurrence risk, we aimed to determine whether GNRI could predict prognosis in patients who underwent PD or DP for resectable pancreatic cancer. This retrospective study examined 139 patients who underwent radical pancreatectomy for resectable pancreatic cancer at Ehime University. All patients were subjected to nutritional screening using GNRI and were followed up for POC diagnosis and patient outcomes such as overall survival (OS). Patients were divided based on the GNRI value of 99 (Low group: N = 74, GNRI < 99; High group: N = 65, GNRI ≥ 99), which was determined by receiver operating characteristic curve analysis. Multivariate analysis showed that GNRI < 99 was statistically correlated with POCs after curative pancreatic resection (p = 0.02). Univariate and multivariate analyses confirmed that GNRI < 99 was significantly associated with long OS (p = 0.04). GNRI could be a potential prognostic marker for resectable pancreatic cancer after curative pancreatic resection despite being a simple and noninvasive approach.

Definition of GNRI. GNRI was measured by body weight, height, and serum albumin. Data obtained before surgical procedure were as follows: GNRI = [14.89 × serum albumin (g/L)] + [41.7 × present/ideal body weight (kg)]. The ideal body weight was defined as 22 × patient height (m) 2 . If the current body weight was higher than the ideal body weight, the present/ideal body weight was 1 12 .
Perioperative management and follow-up study. All patients preoperatively underwent routine blood tests-including serum albumin and tumor marker assessment-and a physical examination that included the measurement of body weight and height. Prophylactic antibiotics were administered through a peripheral vein before anesthetic induction. All patients who underwent DP or PD under general anesthesia received proton pump inhibitors. Amylase values from ascitic fluid obtained from the drainage tube were measured on postoperative days 1, 2, 3, 5, and 7 until removing the drains. Furthermore, dynamic computed tomography was performed to evaluate fluid collections before decannulation of the drainage tubes. Almost all patients were followed up every three months in the first two years and every six months in the following 3-5 years.
In addition, most patients undertook adjuvant chemotherapy due to S-1 for 6 months. The follow-up period started on the date of surgical procedure and ended on the date of death, at the last follow-up, or after a maximum of 60 months. OS was evaluated based on the cause of death as determined from medical records or letters and calculated using the period from the date of surgery to the date of death from any cause or last follow-up. Statistical analysis. All statistical significances were calculated using GraphPad Prism v5.0 (GraphPad Software Inc., La Jolla, CA, USA) and SPSS (SPSS Inc., Chicago, IL, USA). Patient backgrounds were expressed as median and interquartile ranges for nonparametric distribution. Categorical data were expressed as numbers and percentages. On the other hand, statistical significance was determined using Mann-Whitney's U test, χ 2 test, or Fisher's exact test for patient backgrounds and outcomes. A receiver operating characteristic (ROC) curve was analyzed to identify the optimal cutoff value of GNRI for evaluating the risk of POCs. In addition, cutoff value was determined using Youden-Index. OS following pancreatic resection was analyzed by the Kaplan-Meier method, and survival curves were compared using the log-rank test with p-values and 95% confidence intervals (CIs) of hazard ratios (HRs). Univariate and multivariate Cox proportional hazard regression models were used to identify independent prognostic factors affecting OS. A cutoff value for continuous variables was calculated by the respective median. The probability of p < 0.05 was considered statistically significant.

Results
GNRI and clinicopathological features. In this study, 169 patients underwent surgical procedure for pancreatic cancer in the same term. Except for 30 cases of exclusion criteria (total pancreatectomy: 3 patients, Stage 0: 3, Not pancreatic cancer: 8, No information of the prognosis: 16), 139 patients were enrolled. Patients were divided into two groups according to the presence or absence of POCs, which were CD classification 13 ≥ grade IIIa. Table 1 summarizes clinical and demographic data from each group. No statistically significant differences in sex, age, BMI, ASA classification, presence of diabetes mellitus, neoadjuvant chemotherapy, surgical procedures, surgery duration, estimated blood loss, presence of blood transfusions, adjuvant chemotherapy (gemcitabine or S-1 for 6 months), and the completion rate, and time to adjuvant chemotherapy after surgery were observed between patients with (N = 33) and without (N = 106) POC. However, statistically significant differences were observed for preoperative albumin (p < 0.001), surgical procedure (DP or PD; p = 0.04), GNRI values (p < 0.001), and postoperative hospital stays (p < 0.001).
Optimal GNRI cutoff value calculation by ROC curve. The optimal cutoff value for evaluating the risk of POCs was determined using ROC curve analysis (Fig. 1 www.nature.com/scientificreports/ 0.62-0.80), the most appropriate cutoff value was determined to be 99. This value had a sensitivity of 56.6% and a specificity of 78.8%. Patients were then divided into two groups according to the established cutoff value: Low (GNRI < 99, N = 72) and High (GNRI ≥ 99, N = 67) groups. The background profiles were compared between these two groups (Table 2). BMI, preoperative albumin, surgical procedure, and POC rate varied significantly between the two groups. The observed POC rates and the detail in the Low and High groups were 34.7% (N = 25) and 10.4% (N = 7), respectively (Table 3). Univariate analysis revealed that the Low group had a significantly higher rate of POC incidence than the High group (Table 3; p = 0.001).

OS due to the cutoff value of GNRI. Kaplan-Meier analysis and the log-rank test demonstrated that
patients in the Low group had a significantly worse prognosis in terms of OS than those in the High group (p = 0.002; Fig. 2). GNRI value was significantly associated with OS as a prognostic marker. Moreover, Stage II patients were compared according to GNRI cutoff value because they accounted for 77.8% and 70.1% of the Low and High groups, respectively (Fig. 3).    (Table 4).

Discussion
Despite the advanced surgical procedure and perioperative management, POCs after PD or DP (rate: 40-60%) remain a cause of high morbidity in patients with pancreatic cancer 16,17 . The most common major POCs are the development of POPF, DGE, intra-abdominal infection, and PPH. POPF is particularly known as major POC, which is a potentially fatal complication after PD or DP 16,17 . Several studies have reported that POPF was associated with sex, BMI, blood transfusion, pancreatic texture, preoperative biliary drainage, lower serum albumin level, CRP level, and nutritional status 3,18 . However, a definitive risk factor for POPF remains incompletely understood 19 . Generally, POCs have been associated with poor OS, likely due to chemotherapy delay and cancer progression caused by chemokines/cytokines induced POC-associated inflammation in several type of cancers including pancreatic cancer 5,20,21 . Therefore, the primary goal of the surgeons is to prevent these POCs, especially POPF, to reduce poor survival. Previous studies have also reported pancreatic volume, completion of adjuvant chemotherapy, cancer antigen 19-9, carcinoembryonic antigen level, and prognostic index as prognostic factors in patients with pancreatic cancer [22][23][24] .
Recent evidences revealed that nutritional status such as prgnostic nutritional index (PNI) and GNRI are strongly associated with POCs or patients outcomes 25,26 . The PNI is defined using serum albumin and lymphocyte   25 showed that levated PNI is correlated with a better prognosis in head and neck patients. However, AUC was compared with PNI and GNRI using ROC curve analysis. As the result, AUC showed that GNRI was higher than PNI (GNRI: 0.71 vs PNI: 0.60) in this study. On thie other hand, Hayama, et al. 26 reported that lower GNRI was significantly associated with a poor prognosis compared to PNI in elderly patients with colorectal cancer. Thus, we believe GNRI will be better prpgnostic marker than PNI. Using the nutritional status as an objective nutritional screening tool, Bouillanne et al. 12 first reported that GNRI, which includes albumin and BMI, is a prognostic factor of morbidity and mortality in hospitalized elderly patients. Subsequently, several studies have consistently shown that a relationship exists among GNRI, POCs, and cancer prognosis as well since nutritional status was strongly associated with cancer prognosis 25,[27][28][29] . For example, Kushiyama et al. 30 reported that GNRI is associated with POCs after gastrectomy. Furthermore, recent reports revealed that GNRI is an important predictor of POCs and OS in patients with gastric cancer 31,32 . Recent evidence revealed that GNRI is a significant prognostic factor in advanced lung 33 and colorectal 34 cancers. Hu et al., showed that GNRI could be a useful prognostic indicator in patients who underwent surgery 35,36 , notably, in pancreatic cancer.
Previous studies have shown that GNRI is associated with a high risk of POCs, including SSIs, POPF, and PPH after PD or DP [8][9][10][11] . Briefly, a lower GNRI value was related to a higher risk of SSI and reported to be a potential marker for developing POPF and PPH after pancreatic surgery. We have recently reported the role of GNRI as a risk factor for POPFs after DP in 37 patients with pancreatic tumor or invasive gastric cancer 8 and for SSIs after PD in 93 patients with hepatobiliary pancreatic or duodenal cancer 11 . In the present study, we further investigated the predictive value of GNRI for not only the POCs but also long-term postoperative survival after PD or DP in 139 patients with pancreatic cancer treated in a different institution.
In this study, there were 32 patients (23.0%) who developed POCs, including POPF (10.8%), bile leakage (2.9%), PPH (3.6%), and SSIs (7.9%), after PD or DP, which corresponded to CD classification ≥ IIIa and sometimes overlapped. The GNRI value of < 99 was strongly associated with a high risk of POCs, supporting the use of nutritional assessment before an elective procedure. Furthermore, a low GNRI value was significantly associated with poor long-term prognosis. The occurrence of POCs also showed a tendency to deteriorate the OS, although not statistically significant. The development of POCs is considered a potential predictor of worse outcomes because POCs are intimately associated with the delayed induction of adjuvant chemotherapy. In addition, a preoperative poor nutritional condition reflected by a lower GNRI value can affect the postoperative recovery, tolerance for adjuvant chemotherapy, and antitumor immune defense. The exact mechanisms underlying the association between lower GNRI and poorer survival outcome should be determined in further studies. However, some reports showed that body weight or nutritional status were associated with worse prognosis in pancreatic cancer patients, which evidence strongly supported our result 34,35 . At present, our results are consistent with those of a previous study on several cancer [36][37][38] . Moreover, their cutoff values were close to present study, although one of them was age restricted study 39 . Thus, present study strengthened that GNRI might be useful predictor for prognosis in patients with pancreatic cancer who underwent radical surgery.
Our study has several limitations in terms of the interpretation of the study results. First, there was a lack of statistical power caused by the relatively small sample size. Second, our data were collected at a single center. The third limitation lies in the retrospective nature of the study. Finally, present study cannot break the racial line, because only asian data have been reprted. Therefore, a more comprehensive large-scale prospective study should be conducted in the future to validate our study findings.
Finally, we believe that although GNRI can be easily acquired from preoperative routine work without an invasive procedure, it can predict OS in patients with pancreatic cancer after pancreatic resection. Therefore, future prospective randomized studies are warranted to investigate the significance of GNRI for improving outcomes in patients with pancreatic cancer after curative surgery.

Data availability
The data is available from the corresponding author on reasonable request.